Ceralasertib + Trastuzumab Deruxtecan for Solid Tumors

Recruiting at22 trial locations

Overseen by Kanwal P. Raghav

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A inhibitors, Chloroquine

Disqualifiers: Interstitial lung disease, Myocardial infarction, Uncontrolled infection, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

The dose escalation phase of this trial identifies the safety, side effects and best dose of ceralasertib (AZD6738) when given in combination with trastuzumab deruxtecan (DS-8201a) in treating patients with solid tumors that have a change (mutation) in the HER2 gene or protein and have spread to other places in the body (advanced). The dose expansion phase (phase Ib) of this trial compares how colorectal and gastroesophageal cancers with HER2 mutation respond to treatment with a combination of ceralasertib and trastuzumab deruxtecan versus trastuzumab deruxtecan alone. Ceralasertib may stop the growth of tumor cells and may kill them by blocking some of the enzymes needed for cell growth. Trastuzumab deruxtecan is a monoclonal antibody, called trastuzumab, linked to a chemotherapy drug, called deruxtecan. Trastuzumab attaches to HER2 positive cancer cells in a targeted way and delivers deruxtecan to kill them. Ceralasertib and trastuzumab deruxtecan may be safe, tolerable and effective in treating patients with advanced solid tumors expressing the HER2 protein or gene.

Do I need to stop my current medications to join the trial?

The trial requires a washout period (time without taking certain medications) for some treatments before starting the study. Specifically, you must stop taking strong CYP3A inhibitors and certain other medications for a specified time before enrollment. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

What data supports the effectiveness of the drug Ceralasertib + Trastuzumab Deruxtecan for solid tumors?

Trastuzumab deruxtecan has shown effectiveness in treating various HER2-positive cancers, such as breast and gastric cancer, with patients experiencing significant responses. It has been approved for use in HER2-positive breast cancer after other treatments have failed, indicating its potential effectiveness in similar conditions. ^{1 2 3 4 5}

What is the safety profile of Trastuzumab Deruxtecan (Enhertu) in humans?

Trastuzumab Deruxtecan (Enhertu) has been shown to have a generally manageable safety profile in humans, with common side effects including blood and stomach-related issues. However, it carries warnings for lung disease and potential harm to unborn babies, so careful monitoring is needed. ^{1 3 4 6 7}

What makes the drug Ceralasertib + Trastuzumab Deruxtecan unique for treating solid tumors?

This drug combination is unique because it includes Trastuzumab Deruxtecan, a novel antibody-drug conjugate that targets HER2 (a protein that can promote the growth of cancer cells) and delivers a potent chemotherapy directly to the cancer cells, potentially improving effectiveness while limiting damage to healthy cells. ^{1 2 3 4 6}

Research Team

Kanwal P. Raghav

Principal Investigator

University of Texas MD Anderson Cancer Center LAO

Eligibility Criteria

Adults with advanced solid tumors expressing HER2, who've tried at least one chemotherapy, can join this trial. They must have a measurable tumor and be able to undergo biopsies. Key health requirements include proper liver and kidney function, controlled HIV if present, no severe heart issues or lung disease like ILD/pneumonitis, and not pregnant.

Inclusion Criteria

Must have life expectancy of at least 3 months

Patients must have a biopsiable lesion and provide consent for on treatment biopsy

I am fully active or restricted in physically strenuous activity but can do light work.

Exclusion Criteria

Patients with psychiatric illness/social situations that would limit compliance with study requirements

You have had strong allergic reactions to the drug or its inactive parts in the past.

Patients with substance abuse or any other medical conditions that would increase the safety risk to the subject or interfere with participation of the subject or evaluation of the clinical study in the opinion of the investigator

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Evaluate safety, tolerability, and recommended phase 2 dose of trastuzumab deruxtecan in combination with ceralasertib in advanced solid tumors with HER2 expression.

21 days per cycle

1 visit per cycle (in-person)

Dose Expansion

Assess differential pharmacodynamic profile of tumor tissue between Top1 inhibition and dual inhibition of Top1 and ATR in patients with colorectal and gastroesophageal cancer with HER2 expression.

21 days per cycle

1 visit per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

5 years

Every 3 months for 2 years, then every 6 months for 3 years

Treatment Details

Interventions

• Ceralasertib (Enzyme Inhibitor)
• Trastuzumab Deruxtecan (Monoclonal Antibodies)

Trial Overview The DASH trial is testing the combination of two drugs: DS-8201a (trastuzumab deruxtecan) which targets HER2 cancer cells with attached chemo drug deruxtecan; and AZD6738 (ceralasertib), which may halt tumor growth by blocking certain enzymes. The study has two phases to determine safety and compare responses in colorectal/gastroesophageal cancers.

Participant Groups

Group I: Treatment (trastuzumab deruxtecan, ceralasertib) Experimental Treatment 8 Interventions

Patients receive trastuzumab deruxtecan IV over 30-90 minutes on day 1 of each cycle and ceralasertib PO BID on days 1-7 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. NOTE: During the dose-expansion phase, the first 6 patients in each disease cohort (gastroesophageal cancer \[cohort A\] and colorectal cancer \[cohort B\]) receive only trastuzumab deruxtecan for the first cycle, followed by trastuzumab deruxtecan and ceralasertib together in subsequent cycles. Additionally, patients undergo tissue biopsy on study and blood sample collection, CT or PET/CT and ECHO or MUGA throughout the study.

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Dr. Douglas R. Lowy

National Cancer Institute (NCI)

Chief Executive Officer since 2023

MD from New York University School of Medicine

Dr. Monica Bertagnolli

National Cancer Institute (NCI)

Chief Medical Officer since 2022

MD from Harvard Medical School

Findings from Research

Trastuzumab deruxtecan (ENHERTU®) is an innovative treatment that combines an antibody targeting HER2 with a DNA topoisomerase I inhibitor, specifically designed for HER2-expressing solid tumors, including various types of cancer.

It received accelerated approval in the USA based on the promising results from the phase 2 DESTINY-Breast01 trial, which focused on patients with advanced HER2-positive breast cancer who had already undergone multiple treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan: First Approval. Keam, SJ.[2020]

In a phase 2 study involving 184 patients with HER2-positive metastatic breast cancer who had previously been treated with trastuzumab emtansine, trastuzumab deruxtecan demonstrated a significant response rate of 60.9%, with a median response duration of 14.8 months.

While trastuzumab deruxtecan showed promising efficacy, it was associated with notable adverse effects, including interstitial lung disease in 13.6% of patients, highlighting the need for careful monitoring of pulmonary symptoms during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. Modi, S., Saura, C., Yamashita, T., et al.[2021]

In a phase 1 trial involving 44 patients with HER2-positive gastric or gastro-oesophageal junction cancer, trastuzumab deruxtecan demonstrated a manageable safety profile, with the most common serious side effects being anemia and decreases in blood cell counts, but no drug-related deaths were reported.

The treatment showed promising preliminary activity, with 43.2% of patients achieving a confirmed objective response, indicating its potential effectiveness in patients who had previously been treated with trastuzumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive gastric cancer: a dose-expansion, phase 1 study. Shitara, K., Iwata, H., Takahashi, S., et al.[2020]

In a phase 1 trial involving 115 patients with HER2-positive breast cancer previously treated with trastuzumab emtansine, trastuzumab deruxtecan demonstrated a manageable safety profile, with 59.5% of patients achieving a confirmed objective response.

Despite some serious treatment-emergent adverse events, including cases of interstitial lung disease and pneumonitis, the preliminary efficacy results suggest that trastuzumab deruxtecan is a promising treatment option, warranting further investigation in larger clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive breast cancer previously treated with trastuzumab emtansine: a dose-expansion, phase 1 study. Tamura, K., Tsurutani, J., Takahashi, S., et al.[2020]

Trastuzumab deruxtecan has shown efficacy in treating patients with unresectable or metastatic HER2-mutated non-small-cell lung cancer (NSCLC), as demonstrated in the DESTINY-Lung01 and DESTINY-Lung02 trials.

This report presents the first case of a patient with metastatic HER2-amplified NSCLC who achieved a durable response to trastuzumab deruxtecan, suggesting potential effectiveness in this specific patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metastatic HER2-amplified non-small-cell lung cancer treated with trastuzumab deruxtecan. Yun, KM., Bazhenova, L.[2023]

Trastuzumab deruxtecan (Enhertu®) has been shown to significantly improve progression-free survival in adults with unresectable or metastatic HER2-positive breast cancer compared to the previous standard treatment, trastuzumab emtansine, in a pivotal phase 3 trial.

The treatment has a generally manageable safety profile, although it is associated with common adverse events like hematological and gastrointestinal disorders, and requires careful monitoring for interstitial lung disease (ILD)/pneumonitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan: A Review in Unresectable or Metastatic HER2-Positive Breast Cancer. Nie, T., Blair, HA.[2023]

Trastuzumab deruxtecan (Enhertu®) has been shown to be significantly more effective than standard chemotherapy in improving overall survival and achieving objective responses in adults with advanced HER2-positive gastric or gastro-oesophageal junction adenocarcinoma, based on results from the phase II DESTINY-Gastric01 trial.

The treatment is generally well-tolerated, with common side effects including nausea and fatigue, but it does carry important safety warnings for interstitial lung disease and embryo-foetal toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan: A Review in Gastric or Gastro-Oesophageal Junction Adenocarcinoma. Kang, C.[2023]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan: First Approval. [2020]

2. United States pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive gastric cancer: a dose-expansion, phase 1 study. [2020]

4. England pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive breast cancer previously treated with trastuzumab emtansine: a dose-expansion, phase 1 study. [2020]

5. England pubmed.ncbi.nlm.nih.gov

Metastatic HER2-amplified non-small-cell lung cancer treated with trastuzumab deruxtecan. [2023]

6. France pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan: A Review in Unresectable or Metastatic HER2-Positive Breast Cancer. [2023]

7. France pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan: A Review in Gastric or Gastro-Oesophageal Junction Adenocarcinoma. [2023]